Isoxazoline derivatives represented by the general formula (1)
wherein Ar1 represents an aryl group which may be substituted; Ar2 represents another aryl group, which may be substituted as well, and may or may not be the same as Ar1; R represents electron withdrawing group including but not limited to alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, cyano, alkylcarbonyl, arylcarbonyl, formyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl or arylsulfonyl are compounds that are widely used in the field of agriculture. One particular example of the isoxazoline derivatives is ethyl 5,5-diphenyl-3-isoxazolinecarboxylate (commercially known as isoxadifen-ethyl) which is used as a safener in a herbicide for corn production (WO 01/54501/A2 by Syngenta participations AG) and as an insecticide (WO 2006/8110 A1 by Bayer cropscience AG). The estimated worldwide annual consumption of isoxadifen-ethyl is 800 to 1000 tons.
Heretofore, the isoxazoline derivatives represented by the formula (1) are generally prepared through dipolar [2+3] cycloaddition of the corresponding alkenes represented by the general formula (2)
and 1-chloro-oxime represented by the general formula (3) (DE 4331448 A1 19950323)
wherein Ar1, Ar2 and R are as defined above.
Another prior art process for preparing the isoxazoline derivatives represented by the formula (1) is the [2+3] dipolar cycloaddition of alkenes represented by the formula (2) with nitro compounds represented by the general formula (4) (Tetra. Asymmetry, 2008, 19, 2850-2855)
wherein R is as defined above.
These two processes to prepare the isoxazoline derivatives are generally well-known in the prior art. However, the disadvantages of the processes are also generally recognized in the field, particularly for preparing ethyl 5,5-diphenyl-3-isoxazolinecarboxylate:
A) Both of these two processes are low efficiency: through these processes the isoxazoline derivative is produced in modest yield (86% yield using one equivalent of ethyl 2-chloro-2-hydroxyiminoacetate and 1.5 equivalents of 1,1-diphenylethene (DE 4331448 A1 19950323), and 75% yield when the nitro compound used (Tetra. Asymmetry, 2008, 19, 2850-2855).
B) The materials used in these processes are expensive because they have to be made in two or three steps from more common materials; for example, the alkenes, 1,1-diphenylethene represented by the general formula (2), wherein Ar1, Ar2 are phenyls, is commonly made by the reaction of the corresponding diphenyl ketone and the Grignard reagent in an anhydrous pyrophoric ethereal solvent, followed by dehydration with strong acid; and the ethyl 2-chloro-2-hydroxyiminoacetate represented by the general formula (3), wherein R is ethoxycarbonyl, is generally prepared from glycine via esterification with large excess of thionyl chloride, a process through which a large quality of hydrogen chloride and sulphur dioxide are released; followed by oxidation with nitrite under acidic conditions, and the ethyl 2-chloro-2-hydroxyiminoacetate was obtained in only 55-76% overall yield (Bulletin of the Chemical Society of Japan, 1971, 44, 219); and the synthesis of the nitro compounds (4) is achieved in 60-78% yield through nitration of ethyl acetoacetate with fumic nitric acid in acetic anhydride (U.S. Pat. No. 5,162,572 A1 1992). Overall, the existing processes for producing the isoxazoline derivatives represented by the general formula (1) are of low efficiency, highly expensive, and environmentally costly. As a result, there is real need for a novel cost-effective process to improve the production yield and ease the environmental concern.
Cyclopropane derivatives with vicinal electron donor and acceptor substituents are able to be subjected to heterolytic ring cleavage to form 1,3 zwitterionic intermediates (Reissig, H.-U. Topics of Current Chemistry, 144, 73, 1988). In particular, when treated with unsaturated electrophiles they undergo [2+3] type reactions to form five membered carbon or heterocyclic compounds (Shimada, S.; Hashimoto, Y.; Sudo, A.; Hasegawa, M.; Saigo, K. Journal of Organic Chemistry, 57, 7126, 1992; Graziano, M. L.; Isece, M. R.; Cermola, F. Journal of Chemical Research, (S) 82, (M) 0622, 1996). Among these unsaturated electrophiles, nitrosylation reagents including NOCl, NOBr, NOBF4, NaNO2—CF3CO2H have been reported to react with cyclopropane derivatives to form isoxazoline derivatives or/and isoxazodine derivatives: cyclopropane derivatives that have been reported to react with NOCl include ethyl 2,2-dimethoxycyclopropanyl carboxylate, ethyl 2,2-dimethoxy-3,3-dimethylcyclopropanyl carboxylate, ethyl 2-ethoxy-cyclopropanyl carboxylate, ethyl 2,2-dimethoxy-3-methylcyclopropanyl carboxylate (Cermola, F.; Gioia, L. D.; Graziano, M. L.; Isece, M. R.; Journal of Chemical Research 677-681, 2005); cyclopropane derivatives that have been reported to react with NOBF4 include ethyl 2-ethoxy-cyclopropanyl carboxylate (Cermola, F.; Gioia, L. D.; Graziano, M. L.; Isece, M. R.; Journal of Chemical Research 677-681, 2005), 1,1-dichloro-2-arylcyclopropane (Lin, S.-T.; Kuo, S.-H.; Yang, F.-M. Journal of Organic Chemistry, 62, 5229, 1997), 1-aryl-2-arylcyclopropane (Mizuno, K.; Ichinose, N.; Tamai, T.; Otsuji, Y. Journal of Organic Chemistry, 57, 4669-4675, 1992), phenylcyclopropane (Kim, E. K.; Kochi, J. K. Journal of American Chemical Society, 113, 4962, 1991); cyclopropane derivatives that have been reported to react with NaNO2—CF3CO2H include ethyl 2-arylcyclopropanyl carboxylate (Kadzhaeva, A. Z.; Trofimova, E. V.; Fedotov, A. N.; Potekhin, K. A.; Gazzaeva, R. A.; Mochalov, S. S.; Zefirov, N. S. Journal of Heterocyclic Compounds 45, 595, 2009). However, examples presented in these publications listed above clearly demonstrate that the reaction of nitrosylation reagents and cyclopropanes is not feasible as a method for preparing isoxazoline derivatives, as the reaction generally delivers a mixture composed of the desired isoxazoline derivatives, isoxazlidine derivatives and other non-cyclic compounds. And the desired isoxazoline derivatives were generated only in low yields.
This invention discloses a novel process to prepare isoxazoline derivatives represented by the general formula (1) in high efficiency from easy accessible materials. Therefore, it addresses the need for a more cost-effective and more environmentally friendly technology for the synthesis process. This need is solved by the subject matter disclosed herein.